The fundamental feature of all neurodegenerative diseases is neuronal loss affecting selectively vulnerable neuronal populations. In Alzheimer's disease (AD) neuronal loss is accompanied by neurofibrillary tangles (NFTs) composed of abnormal tau proteins. We hypothesize that NFTs are a reflection of fundamental cytoskeletal aberrations, possibly related to alterations in calcium homeostasis, and that cytoskeletal pathology is directly involved in neuronal and synaptic loss in AD. The focus of this research will be to explore the relationship of neurodegeneration and cytoskeletal pathology, especially as it relates to abnormalities of tau protein. A stereotypic pattern neurofibrillary degeneration permits neuropathological staging of AD based upon the topographic distribution of NFTs. The clinical correlates of these stages of neurofibrillary degeneration are integral to the present proposal. While the diagnostic staging is upon NFTs, which are end-stage neuronal alterations, it is our hypothesis that more subtle neuronal alterations that precede NFTs will also be useful in staging AD. We will explore how well these other measures follow the topographic distribution of NFTs and how well they correlate with clinical cognitive measures. Our approaches is two fold-to study factors that are relevant to neurodegeneration in various neuroanatomical regions that are vulnerable regions that are vulnerable to NFTs within individuals brains and to perform similar analyses in brains of individuals spanning the range from normal to advanced AD. At a minimum these studies will establish the pattern of changes of various markers of interest in brains of clinically well-characterized individuals. They may also provide insight into basic processes that underlie selective neuronal vulnerability in AD. The specific molecular probes are rational markers for steps in a cascade of cellular changes that culminate in NFTs, neuronal death and synaptic loss. The markers evaluate changes in cytoskeletal proteins (tau protein), cell cycle proteins, calcium- activated proteases, glycosaminoglycans and presynaptic nerve terminal proteins. The proposed studies will provide information about the relation of changes in these various parameters to each other and with disease progression. The additional benefits of performing these analyses on subjects on whom clinical information is available offers the prospect of detecting markers of early disease that may eventually improve diagnosis and treatment.